期刊
OPEN BIOLOGY
卷 7, 期 10, 页码 -出版社
ROYAL SOC
DOI: 10.1098/rsob.170133
关键词
chemokine; glycosaminoglycan; CXCL13; heparan sulfate binding site; heparan sulfate sequence
资金
- Agence Nationale de la Recherche [ANR-13-BSV3-0010-04-Chemimmmun]
- FRISBI [ANR-10-INSB-05-02]
- GRAL within the Grenoble Partnership for Structural Biology [ANR-10-LABX-49-01]
- National Institutes of Health [HL107152]
- National Center for Research Resources [S10 RR027411]
- China Scholarship Council
Chemokines promote directional cell migration through binding to G-protein-coupled receptors, and as such are involved in a large array of developmental, homeostatic and pathological processes. They also interact with heparan sulfate (HS), the functional consequences of which depend on the respective location of the receptor-and the HS-binding sites, a detail that remains elusive for most chemokines. Here, to set up a biochemical framework to investigate how HS can regulate CXCL13 activity, we solved the solution structure of CXCL13. We showed that it comprises an unusually long and disordered C-terminal domain, appended to a classical chemokine-like structure. Using three independent experimental approaches, we found that it displays a unique association mode to HS, involving two clusters located in the a-helix and the C-terminal domain. Computational approaches were used to analyse the HS sequences preferentially recognized by the protein and gain atomic-level understanding of the CXCL13 dimerization induced upon HS binding. Starting with four sets of 254 HS tetrasaccharides, we identified 25 sequences that bind to CXCL13 monomer, among which a single one bound to CXCL13 dimer with high consistency. Importantly, we found that CXCL13 can be functionally presented to its receptor in a HS-bound form, suggesting that it can promote adhesion-dependent cell migration. Consistently, we designed CXCL13 mutations that preclude interaction with HS without affecting CXCR5-dependent cell signalling, opening the possibility to unambiguously demonstrate the role of HS in the biological function of this chemokine.
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